WO1995012620A1 - Sequestrant d'acide biliaire polyosidique transforme en derive utilise pour abaisser le taux de cholesterol - Google Patents

Sequestrant d'acide biliaire polyosidique transforme en derive utilise pour abaisser le taux de cholesterol Download PDF

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Publication number
WO1995012620A1
WO1995012620A1 PCT/US1994/012503 US9412503W WO9512620A1 WO 1995012620 A1 WO1995012620 A1 WO 1995012620A1 US 9412503 W US9412503 W US 9412503W WO 9512620 A1 WO9512620 A1 WO 9512620A1
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Prior art keywords
bile acid
polysaccharide
ligand
acid sequestrant
derivatized
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PCT/US1994/012503
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English (en)
Inventor
Gary R. Ostroff
Thomas T. Stevenson
Jinsheng Liang
Manssur Yalpani
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Alpha-Beta Technology, Inc.
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Priority to AU81298/94A priority Critical patent/AU8129894A/en
Publication of WO1995012620A1 publication Critical patent/WO1995012620A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof

Definitions

  • LDL low density lipoprotein
  • bile acid sequestrants can be used to treat hypercholesterolemia by binding bile acids in the intestine, carrying them through the small intestine and causing them to be excreted in the feces. Since the bile acid salts are not reabsorbed, the conver ⁇ sion of cholesterol to bile acids is accelerated to main- tain a constant pool of bile acids causing a concomitant decrease in blood cholesterol level. Thus, bile acid sequestrants are widely recognized as therapeutics for the treatment of elevated plasma lipids.
  • Cholestyramine which is a synthetic anion exchange resin based on a styrene-divinylbenzene copolymer, has been shown to inhibit the reabsorption of bile acids, to alter the composition of the LDL particle thereby enhanc ⁇ ing its affinity for the LDL receptor, and to increase uptake and degradation of LDL.
  • cholestyramine can lower cholesterol by up to 40 percent, it is difficult to maintain a patient on a strict cholesterol lowering regimen with cholestyramine due to its offensive taste and frequent side effects of constipation and nausea. Studies indicate that only approximately two percent of the pa- tients who are initially prescribed cholestyramine contin ⁇ ue to take the drug after two months.
  • insoluble synthetic materials include poly ⁇ mers derived from poly(diallylmethylamine) derivatives (Buntin et a_l. , U.S. Pat. 4,759,923); metal coordinated synthetic polyamines derived from poly(methyl acrylates) (St. Pierre et a_l. , U.S. Pat. 5,114,709); and vinylimida- zole ethylene glycol dimethacrylate copolymers (Pirclo et al. ⁇ Eur. Pat. Appl. Al 0,162,388).
  • Soluble derivatives such as those based on quaterna ⁇ ry poly[ (alkylimino)alkylene] polymers or poly(diallyl- methyl ammonium chloride) derivatives, have also been reported, but were found to be toxic in mammals (U.S. Pat. 4,027,009) .
  • the disadvantage of the non-systemic synthetic cho ⁇ lesterol lowering agents is their unfavorable amine odor or palatability characteristics (grittiness, sand-like outhfeel) .
  • the solids of such compositions e.g., cholestyramine
  • the natural materials also tend to absorb substantial amounts of water, resulting in gel-like materials with concomitant gastrointestinal pain, nausea, undesirable bloating, flatulence and laxation potential.
  • Others do not have an approved regulatory status and may have unde ⁇ sirable side effects, such as complexation of essential proteins and hormones.
  • Still others e.g., guar gum
  • guar gum are not uniform products and display variable viscosities which may affect their pharmacological properties.
  • the dosage required for efficacy has been another drawback of fiber- or resin-based cholesterol lowering drugs. Large quantities of bile acid sequestration drugs are typically required to effect a meaningful decrease in lipoprotein plasma levels. This high dosage discourages patient compliance.
  • This invention pertains to novel derivatized polysac ⁇ charide bile acid sequestrant compounds, to compositions containing the novel bile acid sequestrants and to methods for using and making the novel bile acid sequestrants.
  • the compounds comprise hydrophobic, cationic ligand(s) coupled to a polysaccharide substrate.
  • Preferred polysac- charide substrates include starch, cellulose and glucan, such as whole glucan particles.
  • the ligand(s) can be an alkylamine or alkanediamine where the N-methylated form of each is preferred. N-Methylated 1, 12-diaminododecane is most preferred.
  • the ligand(s) can be coupled to the oxidized or carboxyalkylated substrate. Periodate oxida ⁇ tion is the preferred oxidation methodology.
  • these compounds have the acquired ability to bind bile acids, as determined by an in vitro bile acid binding assay. Further, these polysac ⁇ charide derivatives have a significantly enhanced ability to reduce total cholesterol, low density lipoprotein cholesterol and triglyceride levels in the blood of hyper- lipide ic hamsters fed a diet containing a bile acid sequestrant of this invention.
  • novel compounds of this invention can be used to lower plasma lipid levels in mammals.
  • the derivatized polysaccharide bile acid se ⁇ questrants have similar or increased potency for lowering cholesterol compared to cholestyramine. They can be administered to mammals in reasonable quantities and are organoleptically acceptable. The properties should im ⁇ prove patient compliance, compared to currently available non-systemic cholesterol lowering regimens.
  • This invention pertains to the discovery of compounds that have the ability to bind bile acids and thus, in turn, reduce plasma lipids (e.g., plasma total cholester ⁇ ol, triglycerides and LDL cholesterol) .
  • These compounds are polysaccharides, which when derivatized, become potent bile acid sequestrants.
  • the derivatized polysaccharide bile acid sequestrants of this invention comprise li- gand(s) having hydrophobic and cationic moieties chemical ⁇ ly coupled to a polysaccharide substrate.
  • Suitable poly ⁇ saccharide substrates are polysaccharides that can be derivatized; i.e., coupled to the ligand(s) .
  • polysaccharides can also be used.
  • suitable polysaccharides include but are not limited to cellulose, starch, chitosan, guar gum, carrageenan, agar, alginate, a ylose, amylopectin, curdlan, dextran, dextrin, glycogen, laminarin, psyllium, pustulan, nigeran, konjac gluco- mannan, pectin, cyclodextrin and bran.
  • the polysaccharide substrate is a whole glucan particle, cellulose or starch.
  • a whole glucan particle is a glucan which maintains the intact, three-dimensional .in vivo morphology of the cells from which it is derived, such as yeast cell walls.
  • the ligand should be a chemical moiety that has hydrophobic and cationic moieties.
  • the hydrophobic region can contain from about 6 to about 18 carbon atoms.
  • the ligand can be an alkylamine (e.g., hexyl- amine) or an alkanediamine (e.g., 1,6-diaminohexane and 1, 12-diaminododecane) .
  • the carbon atom chain length should be at least about 6 carbons with the upper limit being about 18, with about 6 to about 12 carbon atoms being preferred for alkylamine and alkanediamine moieties.
  • the ligand(s) can be N-methylated or quaternized after being coupled to the polysaccharide substrate. This can be achieved using well known techniques, such as those techniques described by Sommer et al. , J. Org. Che . , 3_6:824-828 (1971).
  • a multiplicity of ligands can be coupled to the substrate. It is preferred to maximize the number of ligands on the substrate. It has been demonstrated that multiplicity of ligands contributes to the compound's ability to efficiently bind bile acids.
  • the degree of derivatization of the polysaccharide should be at least above about 20%. For alkanediamine derivatives the nitro- gen content of the resulting derivative should be above about 2 percent. Depending upon the polysaccharide sub ⁇ strate selected, it is possible to achieve 100 percent derivatization of the residues. For example, all of the free hydroxyl groups on the glucose residues that comprise cellulose or starch can be derivatized.
  • the compounds of this invention can also be made by chemically attaching ligand(s) of choice to a carbonyl containing polysaccharide.
  • a carbonyl containing polysac ⁇ charide is intended to embrace polysaccharides which naturally contain carbonyl groups (e.g., alginate, pectin, gellan, xanthan, welan) and those generated by oxidation or carboxyalkylation.
  • Examples of oxidation methodologies include but are not limited to periodate oxidation, bro ⁇ mine oxidation and Moffat oxidations and hypochlorite oxidation, using techniques well known in the art.
  • the ligand will be either an alkylamine or an alkanediamine.
  • Other known polysaccharide activation techniques can also be used in addition to those recited above.
  • the compound comprises a whole glucan particle (WGP) which is derivatized with 1,12- diaminododecane (also referred to herein as dodecane- diamine or C12) .
  • WGP-C12M whole glucan particle
  • WGP-C12M WGP-C12
  • M the methylated version
  • the N-methylated version of this compound is preferred over the non-methylated version. It has been shown in Table 2 that the amount of bile acids bound by WGP-C12M is greater than that bound by WGP-C12.
  • the preferred method of coupling the C12 ligand to WGP is by reductive amination to the periodate oxidized polysac ⁇ charide. This method facilitates the coupling of multiple ligands to the whole glucan particles.
  • cellulose is coupled to alkanediamine or alkylamine ligand(s) which can preferably be methylated.
  • the preferred ligand is 1, 12-diaminodo- decane which is N-methylated after coupling to cellulose.
  • This embodiment is referred to herein as cellulose-C12 or cellulose-C12M, where M represents the methylated version.
  • Periodate oxidation is the preferred method for oxidizing cellulose thus enabling essentially all residues on the cellulose substrate to be coupled to dodecanediamine.
  • periodate-oxidized starch can be reductively coupled to alkanediamine or alkylamine ligands which can subsequently be methylated.
  • the pre ⁇ ferred coupled ligand is methylated 1, 12-diaminododecane.
  • This compound is referred to herein as starch-C12 or starch-C12M, where M represents the methylated version.
  • Compounds were prepared and evaluated in vitro for chloride ion exchange capacity and bile acid binding capacity. The results of the chloride ion exchange assay indicate the extent of ligand derivatization. The results of the n vitro bile acid binding assay are predictive of the compound's ability to reduce plasma cholesterol lev ⁇ els. Table 1 shows chloride exchange and taurocholate binding capacities of polysaccharide substrates, with and without the C12 ligand.
  • the non-derivatized polysaccha ⁇ rides demonstrate essentially no chloride exchange or taurocholate binding capacity.
  • whole glucan particles, starch and cellulose are transformed into bile acid sequestrants.
  • the binding capacities were compared to cholestyramine.
  • Table 2 shows the chloride exchange and taurocholate binding capacities of various alkylamine and diaminoal- kanes coupled to periodate-oxidized whole glucan parti ⁇ cles. These derivatized compounds were optionally methyl ⁇ ated. The results indicate that methylation improves taurocholate binding capacity and that the length of the ligand affects both chloride exchange and taurocholate binding capacity.
  • the chloride exchange capacity for non-methylated derivative is assumed to be the same as that of the methylated derivative.
  • Table 3 reports the chloride exchange and taurocho ⁇ late binding capacities of some non-methylated deriva ⁇ tives.
  • the compounds were prepared by four different methods of coupling the ligand (e.g., C12) to the polysac ⁇ charide.
  • the ligand e.g., C12
  • the ability of the compounds to lower plasma lipids in vivo was evaluated by determining percent reduction of total cholesterol, LDL cholesterol and triglycerides in the blood of hyperlipidemic hamsters.
  • Plasma lipids were measured in hamsters fed a high fat diet (HFD) only and those fed a high fat diet with drug intervention. In each case, the plasma lipids were compared to hamsters fed cholestyramine with the high fat diet.
  • the amount of bile acid sequestrant fed to the hamsters (approximately 1.5% of the diet) was equilibrated to cholestyramine which represented 0.5% of the diet in order for adequate compar- ison.
  • Table 4 shows a direct comparison of several methylated and non-methylated polysaccharide derivatives or cholestyramine given to hamsters fed high fat diets. There was no observed reduction of total cholesterol, LDL cholesterol or triglycerides in hamsters fed only the high fat diet. Significant reductions in plasma lipids were achieved in hamsters administered WGP- C12M, compared to cholestyramine. Methylated derivatized polysaccharide bile acid sequestrants showed better reduc- tion than did their non-methylated counterparts.
  • novel derivatized polysaccha ⁇ ride bile acid sequestrants of this invention reduce plasma lipid and lipoprotein levels by increasing the fecal excretion of bile acids and their salts, such as deoxycholate. It is well known that increasing loss of bile salts leads to an increased oxidation of cholesterol to bile acids, decreased levels of lipoprotein (LDL and VLDL) and decreased cholesterol in serum. Based on the mechanism of bile acid binding it is reasonable to expect that the compounds of this invention can play an important role in cholesterol homeostasis.
  • the novel drugs can be administered orally to living animals, e.g., humans, by any suitable means, in any suitable form. For example, the drugs can be incorporated into ordinary foodstuffs and beverages in an amount suffi ⁇ cient to produce the desired clinical effect. The drugs can also be incorporated into pharmaceutical compositions customarily employed for oral administration.
  • compositions containing the drug can be formulated into a liquid suspension or in solid form, for example, tablet, capsule, pill or packaged powder.
  • These compositions can be prepared using pharmaceutically acceptable carriers or diluents, such as, for example, starch, glucose, lactose, gelatin, sucrose, water, aqueous dilute ethanol, propylene glycol, glycerol and sorbitol.
  • Such formulations can also include flavoring and sweeten- ing agents such as fructose, inert sugar, aspartame, cocoa, citric acid, ascorbic acid and fruit juices.
  • Sus ⁇ tained release forms of administration are also accept ⁇ able.
  • the amount administered will vary depending among other things on the size of the animal, the type of animal (e.g., human) and the general health of the animal.
  • the drugs of this invention can be administered in combination with other known drugs which reduce serum cholesterol, such as niacin, competitive inhibitors of HMG-CoA reductase, Probucol and a fibric acid derivative (Ge fibrozil) .
  • drugs which reduce serum cholesterol such as niacin, competitive inhibitors of HMG-CoA reductase, Probucol and a fibric acid derivative (Ge fibrozil) .
  • niacin competitive inhibitors of HMG-CoA reductase
  • Probucol and a fibric acid derivative (Ge fibrozil)
  • a fibric acid derivative Ge fibrozil
  • Aqueous sodium hydrogen carbonate (6 equiva ⁇ lents) was added, followed by solid sodium borohydride (3.6 equivalents). The suspension was stirred overnight and the reaction was quenched with the addition of ace ⁇ tone. The suspension was centrifuged and the supernatant decanted. The pellet was washed with water, followed by ethanol 3 times, giving wet pellet 1. The pellet was fur- ther washed in water 2 times, 2-propanol 2 times and acetone 2 times and dried in vacuo to provide WGP-C12 having a nitrogen content of 4.0%.
  • Example 2 to give cellulose-Cl2M, with a nitrogen content of 5.6%.
  • Example 4 Synthesis of WGP Coupled to Diaminooctane and Diaminodecane
  • Whole glucan particles were oxidized, coupled to the appropriate diaminoalkane and reduced as described in Example 1 and methylated, washed and dried as described in Example 2.
  • Example 5 Synthesis of Cellulose-C6 Cellulose (Sigmacell, type 50) was oxidized, coupled to 1, 6-diaminohexane and reduced as described in Example 1, except that the coupling was performed in water, giving cellulose-C6 with a nitrogen content of 3.9%.
  • Example 6 Synthesis of GP-C6M
  • WGP-C6 was methylated, washed and dried as described in Example 2, giving WGP-C6M with a nitrogen content of 3.4%.
  • Cellulose was oxidized, coupled to 1,6-diaminohexane and reduced as described in Example 5 and methylated, washed and dried as described in Example 2, giving cellu- lo ⁇ e-C6M with a nitrogen content of 2.5%.
  • Example 9 Synthesis of Starch Starch-C12M via Periodate Oxidized Precursor Starch dialdehyde obtained as in Example 1 (10 equiv ⁇ alents) was dispersed in ethanol or aqueous ethanol and treated with 1,12-diaminododecane (3-24 equivalents) for 4 h and subsequently with sodium cyanoborohydride (20 equiv ⁇ alents) for a further period of 4-48 hours.
  • the reduction was performed using sodium borohydride as reductant, with the reductant being added shortly after the alkanediamine ligand.
  • the material was also treated with a cross-linking agent, e.g., epichloro- hydrin (0.01 equivalents).
  • aqueous suspension of whole glucan particles (1 equivalent) was treated with aqueous bromine (0.1M, 1 equivalent) at room temperature. After 15 minutes, NaOH (1.5N) was added to neutralize the suspension, and the neutralization was periodically repeated over the course of 6 hours, before the mixture was filtered, extensively washed with water and 2-propanol, and dried in vacuo at 50°C to give a white product. Alternatively, the oxida ⁇ tion was carried out over longer periods.
  • the oxidized whole glucan particles were then coupled to 1, 12-diaminododecane as described in Example 1 to give the corresponding whole glucan particle-alkanediamine derivatives with nitrogen contents of 2.6%.
  • the glucan- alkanediamine derivatives were subsequently methylated as descried in Example 2.
  • Example 11 Synthesis of Whole Glucan Particle-Alkane- diamine Derivative via Dimethylsulfoxide-Acetic Anhydride Oxidized Precursor
  • a suspension of whole glucan particles (1 equivalent) in dimethylsulfoxide was treated with acetic anhydride (1 equivalent) at room temperature. After 15 minutes addi ⁇ tional solvent was added to dilute the resulting gel-like material, which was then stirred for an additional period of 4-48 hours. The oxidized material was precipitated with acetone, filtered, extensively washed with acetone and dried in vacuo at 50°C.
  • different ratios of oxidant e.g., 0.5 equivalents
  • the oxidized whole glucan particles were then coupled to 1,12-diaminododecane as described in Example 1 to give the corresponding whole glucan particle-alkanediamine derivatives with nitrogen contents of 2.9%.
  • the whole glucan particle-alkanediamine derivatives were subsequent ⁇ ly methylated as described in Example 2.
  • Example 12 Synthesis of Whole Glucan Particle-Alkane- diamine Derivative via Carboxyalkyl Precursors
  • a suspension of whole glucan paricles (1 equivalent) in 50% aqueous NaOH was treated with chloroacetic acid (1 equivalent) dissolved in 2-propanol at room temperature. After stirring for 24 h, another portion of chloroacetic acid (0.3 equivalents) was added, the mixture was stirred for 4 h, extensively dialyzed and lyophylized.
  • the glucan particles (1 equivalent) dispersed in a minimum amount of water were treated with aqueous NaOH (3 equivalents) then treated with chloroacetic acid (1.5 equivalents) , dissolved in methanol at room temperature for 30 h, filtered, washed with alcohol, and dried.
  • Bile acid sequestrant synthesized according to Exam ⁇ ples 1-12 or cholestyramine (10-15 mg) was suspended in aqueous silver nitrate (0.6-0.7 mL, 0.1 M) and water (0.8- 1.0 mL) was added. The suspension was stirred overnight and centrifuged. The supernatant (0.5-0.6 mL) was trans ⁇ ferred to an Erlen eyer flask and diluted with water (15 mL) . Aqueous iron (III) ammonium sulfate (1.0 mL of 2.5 g NH 4 Fe(S0 ) 2 .12H 2 0 dissolved in 25 mL of 6 M nitric acid) was added as an indicator. The resulting solution was titrat ⁇ ed with aqueous potassium thiocyanate (0.005 M) until an orange color persisted for 1 minute.
  • Example 14 Bile Acid Binding Assay by Enzymatic Analysis
  • the in vitro bile acid binding capacity of the com- pounds of this invention was evaluated using an enzymatic method.
  • a reaction solution containing 6.38 g NaHC0 3 , 2.34 g NaCl and 2.24 g KC1 was added to deionized water to a total of 1000 mL.
  • the pH was adjusted to 6.2 with concentrated HC1 (30 mM) .
  • a series of labeled 15 mL screw cap tubes were set up, each tube containing 10.0 mg of either test sample, cholestyramine or underivatized poly ⁇ saccharide; 3.0 mL of 10 mM taurocholate (268.9 mg/50 mL reaction solution) and 3.0 mL of reaction solution.
  • Each tube was capped, mixed and shaken at 37°C for 2 hours. The tubes were then centrifuged at 3000 g for 15 minutes. An 0.1 L aliquot of supernatant was transferred from each tube to a fresh set of tubes (1.5 mL) , and 0.4 mL of water was added to each tube to dilute the supernatant.
  • Each tube was separately analyzed using an enzymatic bile acid assay. Twenty ⁇ l supernatant (sample, control or standard) , 20 ⁇ l Bovine Serum Albumin (HyClone) and 100 ⁇ l test or blank bile acid reagent (Bile Acid Analysis Kit, Sigma #450-A) were combined, mixed well and reacted at 37°C for 10 minutes in a 96 well microtiter plate. Optical density (OD) was read at 550 nm in a THERMO max microplate reader (Molecular Devices) . The taurocholate binding capacity in mmol/g was calculated from the difference in taurocholate concentra ⁇ tion of the supernatant before and after exposure to sequestrant.
  • OD Optical density
  • Polysaccharide derivative was 1.5% of diet; cholestyramine was 0.5% of diet.
  • Polysaccharide derivative was 1.5% of diet.
  • Group 2 0.5% cholestyramine + HFD Group 3: 1.5% cholestyramine + HFD Group 4: 0.2% sequestrant + HFD Group 5: 0.5% sequestrant + HFD Group 6: 1.0% sequestrant + HFD Group 7: 1.5% sequestrant + HFD Group 8: 0.1% sequestrant + HFD Group 9: 0.2% sequestrant + HFD Group 10: 0.5% sequestrant + HFD Group 11: 1.0% sequestrant + HFD
  • Example 3 The sequestrant administered in this study is described in Example 3. Groups 1-7 were fed the above diets for 8 weeks. Groups 8-11 were fed a diet of 1.5% sequestrant and HFD for 4 weeks and then the above diets for the next four weeks.
  • TC total cholesterol
  • FC free cho- lesterol
  • the effect of sequestrant on total cholesterol levels was to decrease the TC concentration in plassma as the amount of sequestrant in the diet increased (Table 8) .
  • the number of hamsters per group was twelve.
  • Fecal bile acids were measured in the control animals (0.64 ⁇ 0.13 mg/day/hamster); animals fed HFD + 1.5% cholestyramine (1.04 ⁇ 0.34 mg/day/hamster); and animals fed HFD + 1.5% sequestrant (3.52 ⁇ 0.71 mg/day/hamster).
  • Hamsters fed cholestyramine had 162% greater fecal bile acid content than control.
  • Animals fed novel sequestrant had 551% greater fecal bile acid content than control. The results show that the novel sequestrant had the abili ⁇ ty to bind and sequester a significantly greater amount of fecal bile acids compared to the same amount of cholestyr ⁇ amine.
  • Plasma samples were diluted on an ELISA plate with 0.9% NaCl.
  • Triglyceride reagent lipoprotein lipase, glycerol kinase, ATP, glycerol phosphate oxidase, 4-amino- antipyrine, peroxidase and sodium-N-ethyl-N-3-sulfopropyl m-anisidine; Product #339, Sigma Chemicals
  • Triglyceride reagent lipoprotein lipase, glycerol kinase, ATP, glycerol phosphate oxidase, 4-amino- antipyrine, peroxidase and sodium-N-ethyl-N-3-sulfopropyl m-anisidine; Product #339, Sigma Chemicals
  • a 96 well ELISA plate was set up in duplicate for each sample and 200 ⁇ L of triglyceride reagent were placed in each well.
  • a 96 well ELISA plate containing 200 ⁇ L of cholesterol reagent cholesterol esterase, cholesterol oxidase, p-hydroxybenzene, sulfonate, 4-aminoantipyrine peroxidase; Product #352, Sigma Chemicals
  • cholesterol reagent cholesterol esterase, cholesterol oxidase, p-hydroxybenzene, sulfonate, 4-aminoantipyrine peroxidase; Product #352, Sigma Chemicals
  • LDL-Cholesterol Amount of LDL-cholesterol was determined as the difference between TC and HDL.

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Abstract

L'invention concerne de nouveaux composés séquestrants d'acide biliaire polyosidique transformés en dérivés, des compositions les contenant et des procédés permettant de les utiliser et de les préparer. Ces séquestrants comprennent au moins un ligand cationique hydrophobe couplé à un substrat polyosidique. Ces composés et compositions s'utilisent pour lier des acides biliaires et pour abaisser le taux de lipides dans le plasma.
PCT/US1994/012503 1993-11-01 1994-10-31 Sequestrant d'acide biliaire polyosidique transforme en derive utilise pour abaisser le taux de cholesterol WO1995012620A1 (fr)

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AU81298/94A AU8129894A (en) 1993-11-01 1994-10-31 Derivatized polysaccharide bile acid sequestrant for reducing cholesterol

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US14622593A 1993-11-01 1993-11-01
US08/146,225 1993-11-01

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Cited By (8)

* Cited by examiner, † Cited by third party
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US5567685A (en) * 1994-08-16 1996-10-22 Yissum Research Development Company Of The Hebrew University Of Jerusalem Water-Soluble polyene conjugate
WO1999061481A1 (fr) * 1998-05-28 1999-12-02 Mediplex Corporation, Korea Derives de polysaccharide amphiphiles
US6011008A (en) * 1997-01-08 2000-01-04 Yissum Research Developement Company Of The Hebrew University Of Jerusalem Conjugates of biologically active substances
WO2000004907A1 (fr) * 1998-07-21 2000-02-03 Alpenstock Holdings Limited Formulation antilipemique
US6258796B1 (en) 1996-11-20 2001-07-10 The University Of Montana Water soluble lipidated arabinogalactan
US8062686B2 (en) 2005-04-12 2011-11-22 InovoBiologics, Inc. Dietary supplement, and methods of use
US8597709B2 (en) 2005-04-12 2013-12-03 Inovobiologic Inc. Dietary supplement and methods of use
ES2579487A1 (es) * 2015-02-11 2016-08-11 Universidad De Granada Uso de polímeros basados en sacáridos entrecruzados como secuestrantes de ácidos biliares

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US6258796B1 (en) 1996-11-20 2001-07-10 The University Of Montana Water soluble lipidated arabinogalactan
US6303584B1 (en) 1996-11-20 2001-10-16 The University Of Montana Water soluble lipidated arabinogalactan
US6011008A (en) * 1997-01-08 2000-01-04 Yissum Research Developement Company Of The Hebrew University Of Jerusalem Conjugates of biologically active substances
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WO1999061481A1 (fr) * 1998-05-28 1999-12-02 Mediplex Corporation, Korea Derives de polysaccharide amphiphiles
GB2342357A (en) * 1998-05-28 2000-04-12 Mediplex Corp Korea Amphiphilic polysaccharide derivatives
WO2000004907A1 (fr) * 1998-07-21 2000-02-03 Alpenstock Holdings Limited Formulation antilipemique
US6706695B2 (en) 1998-07-21 2004-03-16 Alpenstock Holdings Limited Antilipemic formulation
US8062686B2 (en) 2005-04-12 2011-11-22 InovoBiologics, Inc. Dietary supplement, and methods of use
US8597709B2 (en) 2005-04-12 2013-12-03 Inovobiologic Inc. Dietary supplement and methods of use
US10010102B2 (en) 2005-04-12 2018-07-03 Inovobiologic Inc. Dietary supplement and methods of use
ES2579487A1 (es) * 2015-02-11 2016-08-11 Universidad De Granada Uso de polímeros basados en sacáridos entrecruzados como secuestrantes de ácidos biliares

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